Diabetes increases the susceptibility to infectious diseases, including periodontal disease. Periodontal disease is initiated by bacteria, but components of the host immune response are thought to contribute significantly to periodontal tissue damage. Of particular interest, free radicals such as superoxide play a prominent role both in diabetic complications and in periodontal tissue damage. Free radicals are produced in large quantities by polymorphonuclear (PMN) leukocytes, and abnormal PMN function is detected both in diabetes and in periodontal disease. This proposal is intended to help elucidate the molecular mechanisms that link diabetes and periodontal disease. The chief hypothesis to be tested is that elevated blood glucose activates PMN leukocytes, which in turn release excess superoxide causing tissue damage in the periodontium and in other tissues. A second focal point of these experiments is the evaluation of novel endogenous anti-inflammatory lipids, such as lipoxins, resolvins and docosatrienes. These molecules are formed locally during inflammation, and they antagonize the effect of PMN leukocytes and promote resolution of inflammation. Experiments are designed to test the effectiveness of stable analogs of lipoxins, defensins and docosatrienes in decreasing inflammatory tissue damage in diabetes and periodontal disease. These experiments employ a novel animal model of insulin-dependent diabetes, the Akita mice, and another mouse line, the Ncfl mice, whose PMN are deficient in superoxide generation. Akita and Ncf1 mice will be crossed to generate a double mutant experimental model in which the contribution of superoxide to diabetic tissue damage can be analyzed in alveolar bone and in soft tissue. The findings from these experiments might be important not only from the view of periodontal health, but also for diabetes research. Moreover, findings on novel lipid inhibitors of inflammation will be important in evaluating the therapeutic potential of these compounds in resolving inflammation in periodontal and other inflammations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE016933-03
Application #
7255534
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lumelsky, Nadya L
Project Start
2005-09-01
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
3
Fiscal Year
2007
Total Cost
$254,581
Indirect Cost
Name
Boston University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Zamakhchari, Mai F; Sima, Corneliu; Sama, Kishore et al. (2016) Lack of p47(phox) in Akita Diabetic Mice Is Associated with Interstitial Pneumonia, Fibrosis, and Oral Inflammation. Am J Pathol 186:659-70
Ayilavarapu, Srinivas; Kantarci, Alpdogan; Hasturk, Hatice et al. (2014) IPLA2 mRNA expression by human neutrophils in type 2 diabetes and chronic periodontitis. J Int Acad Periodontol 16:121-6
Gao, Li; Faibish, Dan; Fredman, Gabrielle et al. (2013) Resolvin E1 and chemokine-like receptor 1 mediate bone preservation. J Immunol 190:689-94
Herrera, Bruno S; Martins-Porto, Rodrigo; Campi, Paula et al. (2011) Local and cardiorenal effects of periodontitis in nitric oxide-deficient hypertensive rats. Arch Oral Biol 56:41-7
Ayilavarapu, Srinivas; Kantarci, Alpdogan; Fredman, Gabrielle et al. (2010) Diabetes-induced oxidative stress is mediated by Ca2+-independent phospholipase A2 in neutrophils. J Immunol 184:1507-15
Sima, C; Rhourida, K; Van Dyke, T E et al. (2010) Type 1 diabetes predisposes to enhanced gingival leukocyte margination and macromolecule extravasation in vivo. J Periodontal Res 45:748-56
Osuchowski, Marcin F; Craciun, Florin L; Schuller, Elizabeth et al. (2010) Untreated type 1 diabetes increases sepsis-induced mortality without inducing a prelethal cytokine response. Shock 34:369-76
Herrera, B S; Ohira, T; Gao, L et al. (2008) An endogenous regulator of inflammation, resolvin E1, modulates osteoclast differentiation and bone resorption. Br J Pharmacol 155:1214-23
Omori, Kazuhiro; Ohira, Taisuke; Uchida, Yushi et al. (2008) Priming of neutrophil oxidative burst in diabetes requires preassembly of the NADPH oxidase. J Leukoc Biol 84:292-301
Gyurko, Robert; Siqueira, Camille C; Caldon, Nathaniel et al. (2006) Chronic hyperglycemia predisposes to exaggerated inflammatory response and leukocyte dysfunction in Akita mice. J Immunol 177:7250-6